1. Searching for Potential HDAC2 Inhibitors: Structure-activity Relationship Studies on Indole-based Hydroxamic Acids as an Anticancer Agent
- Author
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Jun Dai Faisal Jamshaid, Ademir F. Morel, Yuan-Han Yang, Richa Dayaramani, Dimitri Komiotis, Harish Rajak, Sun-Wung Hsieh, Ming-Wei Liu, Ling-Chun Huang, Meng-Ni Wu, Ajmal Khan, Li Xi Yang, and Sudit Mukherjee
- Subjects
Indole test ,0303 health sciences ,010405 organic chemistry ,Chemistry ,Histone deacetylase 2 ,Pharmaceutical Science ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,03 medical and health sciences ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,030304 developmental biology - Abstract
Aim: To predict the most potent indole based HDAC2 inhibitors from several scientific reports through the process of lead identification and SAR development. Background: The current scenario is observing Histone Deacetylase (HDAC) as an alluring molecular target for the designing and development of drugs for cancer treatment. Background: The current scenario is observing Histone Deacetylase (HDAC) as an alluring molecular target for the designing and development of drugs for cancer treatment. Objective: To identify the lead and establish structure-activity correlation among indole based hydroxamic acid to find out promising HDAC2 based anticancer agent. Methods: A dataset containing 59 molecules was analyzed using structure and ligand-based integrated approach comprising atom-based 3D-QSAR (Quantitative Structure-Activity Relationship) and pharmacophore study, e-pharmacophore mapping and molecular modeling methodologies. The finest model was prepared by amalgamating the properties of electronegativity, polarizability, Vander Waals forces and other conformational aspects. Results: The result of 3D QSAR analysis, performed for 4 PLS factor, provided the following statistical information: R2 = 0.9461, Q2 = 0.7342 and low standard of deviation SD = 0.1744 for hypothesis ADDDH.10 and R2 = 0.9444, Q2= 0.7858 and again low standard of deviation SD = 0.1795 for hypothesis DDHRR.12. The XP molecular docking showed intermolecular interactions of small molecules with amino acids such as GLY154, HIP145, PHE210, HIE183, internal H2O and Zn2+. Conclusion: The interpretation of data generated as a result of this investigation clearly hints about the better biological activity of test compounds as compared to SAHA. Hence, the outcome of these structure and ligand-based integrated studies could be employed for the design of novel arylindole derivatives as a potent HDAC inhibitor.
- Published
- 2020